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Abstract

Background—There is controversy regarding the immediate and long-term effects of PTCA on the coronary flow reserve.

Methods and Results—A total of 54 patients with 1-vessel disease and normal left ventricular function were studied after balloon angioplasty (n=34) or stent implantation (n=20). Distal coronary blood flow velocity reserve (CFR) was defined as the ratio of adenosine-induced hyperemic versus baseline blood flow velocity with a 0.014-in Doppler guidewire. The relative CFR was defined as the ratio of the distal CFR and the reference CFR measured in the normal adjacent coronary artery. Hemodynamic and angiographic measurements were performed before and directly after balloon angioplasty or stent implantation and at 6-month follow-up. CFR after PTCA ≤2.5 was defined as an impaired CFR. Immediately after PTCA, CFR improved toward the range of the reference artery CFR. In both the balloon-treated and the stent-treated groups, initial high CFR values decreased and impaired CFR values increased at follow-up toward the values of the reference CFR in patients without restenosis. Impaired CFR after balloon angioplasty (33%) or stent implantation (58%) in patients without restenosis was related to an increased baseline flow velocity that normalized at follow-up. Patients with an increase of CFR after stenting were characterized by an unaltered baseline flow velocity and an increased adenosine-induced hyperemic flow velocity.

Conclusions—An impaired CFR (≤2.5) is a frequent finding after balloon angioplasty or stent implantation as a result of a high baseline flow velocity. Normalization of impaired CFR at follow-up in patients without restenosis was associated with a decline of the baseline flow velocity after both balloon angioplasty and stent implantation, supporting the contention that this phenomenon relates to a slow recovery of autoregulation of the microvascular bed.

In a classic study, Gould et al1 introduced the curvilinear relationship between coronary lesion severity and flow reserve distal to the narrowing. Subsequently, several clinical studies evaluated this relationship in the setting of coronary angioplasty using digital subtraction techniques,2 intracoronary blood flow velocity and pressure measurements,34 or PET.5 A recently published large, multicenter trial (DEBATE study) demonstrated that impaired coronary flow reserve (≤2.5) immediately after balloon angioplasty was associated with a high incidence of recurrent angina, need for revascularization procedures, and a high restenosis rate.6 The hypothesis that impaired coronary flow reserve after balloon angioplasty is due to residual lumen obstruction was supported by studies showing a normalization of impaired coronary flow reserve after optimal vascular lumen enlargement by stent implantation.78 However, other studies demonstrated a spontaneous improvement of impaired coronary flow reserve after balloon angioplasty without adjunctive coronary intervention due to remodeling of the epicardial lesion9 and/or a slow recovery of autoregulation of the microvascular tone.1011 Consequently, controversy exists regarding the mechanisms involved in the effect of coronary angioplasty on the distal coronary flow reserve. In view of its clinical relevance, we studied the immediate and long-term effects of PTCA on the distal coronary flow velocity reserve (CFR) balloon angioplasty with coronary stent implantation.

Methods

Patients

Patients (mean age, 56±9 years; range, 36 to 73 years) with single native coronary artery disease and normal left ventricular function, referred to our institution for standard balloon angioplasty (n=34) or stent implantation (n=20), were studied prospectively. Written informed consent was given according to the rules of the Institutional Ethics Committee, which approved the study.

Cardiac Catheterization

Therapy with all antianginal medication was continued until cardiac catheterization. Cardiac catheterization was performed in all patients by the percutaneous femoral approach. All patients received heparin 5000 IU IV as a bolus at the beginning of the catheterization. Additional heparin was administered if the procedure lasted >90 minutes.

Quantitative Coronary Angiography

Off-line analysis of the angiographic severity of the coronary narrowing was performed by use of an automated contour detection algorithm (QCA-CMS version 3.32, MEDIS).12 The outer diameter of the fluid-filled guiding catheter, centered, was used as a scaling device to obtain absolute arterial dimensions. Two orthogonal projections of the coronary artery lesion during the end-diastolic phase were used to assess biplane analysis of the minimal lumen diameter (MLD) and the percent diameter stenosis of the coronary narrowing. Angiographic restenosis was defined as a diameter stenosis >50% at follow-up assessed by quantitative coronary angiography (QCA).

Coronary Blood Flow Velocity Analysis

All coronary blood flow velocity measurements with the Doppler angioplasty guidewire (FloWire, EndoSonics) were performed as previously described.13 After on-line assessment of the baseline average peak velocity (APV), hyperemia was induced by administration of an intracoronary bolus of adenosine (12 μg in the right coronary artery; 18 μg in the left coronary artery). CFR was defined as the ratio of the adenosine-induced hyperemic/baseline APV. The reference CFR was determined in an adjacent angiographically normal coronary artery. The relative CFR (rCFR) was defined as the ratio of the distal/reference CFR. An impaired CFR after PTCA was defined as a CFR ≤2.5.6

Study Protocol

Nitroglycerin (0.1 mg IC) was administered every 30 minutes throughout the procedure. A Doppler guidewire was inserted across the coronary narrowing before the first balloon inflation to obtain optimal and stable baseline and adenosine-induced hyperemic coronary blood flow velocity signals. The balloon catheter was advanced over the Doppler guidewire at the site of the coronary narrowing. Consecutive balloon inflations of 1 to 2 minutes’ duration were performed until an angiographically satisfactory result was achieved after a waiting time of 10 minutes. A successful balloon angioplasty was defined as a diameter stenosis <50% by visual assessment. Coronary stents (Palmaz-Schatz, Johnson & Johnson) were implanted under guidance by intravascular ultrasound imaging for optimal deployment against the vascular wall. Angiography was performed after successful balloon angioplasty or stent implantation and at follow-up in the same directions as before balloon angioplasty. Baseline and adenosine-induced hyperemic coronary blood flow velocity measurements were performed at the same location distal to the dilated segment and in an angiographically normal reference coronary artery as well.

Statistical Analysis

Continuous data are presented as mean±SD. χ2 analysis was used to detect a difference in categorical patient characteristics. A 2-tailed paired t test (or Wilcoxon test for nonparametric data) was used to identify variation within subjects. A 2-tailed unpaired t test (or Mann-Whitney test for nonparametric data) was used to assess differences in continuous variables. Forward stepwise linear regression analysis was used to assess the independent explanatory variables for the alterations of the absolute and relative CFRs at follow-up in both the balloon-treated and stent-treated patients. Potential explanatory variables having an association after univariate analysis (P<0.1) were included. A value of P<0.05 was considered statistically significant.

Results

QCA at follow-up (6.7±1.9 months) revealed an absence of restenosis in 27 of the 34 patients enrolled in the balloon-treated group and 19 of the 20 patients included in the stent-treated group. The baseline characteristics of the 46 patients without restenosis at follow-up are shown in Table 1⇓. In both patient groups, heart rate and mean aortic pressure did not change in individual patients during the procedure (Table 2⇓).

QCA and Coronary Blood Flow Velocity Data in Patients Without Restenosis at Follow-Up

QCA Data in Patients Without Restenosis at Follow-Up

Standard balloon angioplasty and high-pressure stent implantation (14±3 bar) resulted in a direct improvement of the angiographic variables (Table 2⇑). Follow-up in the stent-treated patient group revealed a reduction of the arterial dimensions. However, all angiographic luminal dimensions were larger at follow-up in the stent-treated group than in the balloon-treated group (Table 2⇑).

Blood Flow Velocity Data in Patients Without Restenosis

The reference CFR of the normal coronary artery after PTCA was 3.3±0.4 in the balloon-treated patients and 3.2±0.7 in the stent-treated patients and did not change at follow-up in either of the patient groups (3.2±0.6 and 3.0±0.4, respectively).

CFR and rCFR increased after standard balloon angioplasty (Table 2⇑). Stent implantation resulted in a significant increase in adenosine-induced hyperemic blood flow velocity but did not yield an increase in CFR and rCFR as a result of a nonsignificant increase in baseline blood flow velocity (Table 2⇑).

When the pooled data before balloon angioplasty and at follow-up were used, the overall linear relationship between CFR and rCFR in the both patient groups, including patients with restenosis, was strong (r=0.93, Figure 1⇓). An absolute CFR cutoff value of 2.5 was in accordance with a relative CFR cutoff value of 0.80 (Figure 1⇓).

Overall linear relationship between absolute CFR and rCFR of both balloon-treated (BA) and stent-treated (stent) patient groups, including patients with restenosis, using pooled data before PTCA and at follow-up. CFR value of 2.5 was in accordance with rCFR value of 0.80.

Normalization of the CFR and rCFR at Follow-Up in Patients Without Restenosis

Balloon-treated patients demonstrated similar CFR and rCFR at follow-up, as measured directly after balloon angioplasty (Table 2⇑). However, a correlation between the CFR of the dilated vessel and the CFR of the normal reference vessel was absent after balloon angioplasty (Figure 2A⇓). This correlation improved at follow-up (r=0.63, Figure 2B⇓) as a result of alterations of the CFR of the dilated vessel. When all patient characteristics, angiographic and hemodynamic variables, and their changes at follow-up were used, stepwise regression analysis revealed the CFR after balloon angioplasty (r=−0.74, P<0.0001; Figure 3⇓) and the alterations of the reference CFR at follow-up (r=0.39, P=0.07) to be the only independent explanatory variables for the alterations of the CFR at follow-up (y=2.1−0.70×CFR after balloon angioplasty+0.67×alterations of the reference CFR at follow-up, r2=0.79, P<0.0001). The rCFR immediately after balloon angioplasty was the sole independent variable for the alterations of the rCFR at follow-up (r=−0.82, P<0.0001; Figure 3⇓). The CFR after stent implantation was lower than the reference CFR (3.2±0.7), whereas it was in the range of the reference CFR at follow-up. The relationship between CFR and reference CFR was moderate after stent placement (Figure 2C⇓) and slightly improved at follow-up (Figure 2D⇓). After stepwise regression analysis, alterations of the CFR during follow-up were explained by the CFR immediately after stent implantation (r=−0.93, P<0.0001; Figure 3⇓). The rCFR after stent implantation was the only explanatory variable for the alterations of the rCFR during follow-up after stepwise regression analysis. The regression lines of the CFR and rCFR were similar in stent-treated and balloon-treated patient groups (Figure 3⇓).

Left, Relationship between CFR immediately after PTCA and alterations of CFR at follow-up (ΔCFR at follow-up) in both balloon-treated (BA; r=−0.74, P<0.0001) and stent-treated (stent; r=−0.92, P<0.0001) patients without restenosis. Right, Relationship between rCFR and alterations of rCFR at follow-up (ΔrCFR) in both balloon-treated (r=−0.82, P<0.0001) and stent-treated (r=−0.85, P<0.0001) patients without restenosis.

Impaired CFR After Balloon Angioplasty

Of all 54 patients, 23 (43%) demonstrated impaired CFR (≤2.5) immediately after balloon angioplasty; of these 23 patients, 14 did not receive adjunct stent implantation. Five of these 14 patients of the balloon-treated group developed angiographic restenosis at late follow-up. The 9 patients without restenosis at follow-up demonstrated a nonsignificant increase of CFR (P=0.07) and a significant increase of rCFR during follow-up (P<0.05; Table 3⇓). Baseline APV after balloon angioplasty in the balloon-treated patient group was higher in patients with impaired CFR than in patients without impaired CFR after balloon angioplasty (Figure 4⇓, Table 3⇓). There were no other angiographic or hemodynamic differences (Table 3⇓) between the two groups.

Baseline blood flow velocity (left) and adenosine-induced hyperemic blood flow velocity (right) measured before balloon angioplasty, after balloon angioplasty (BA), after stenting (stent), and at follow-up are illustrated in both balloon-treated patients (top) and stent-treated patients (bottom) without restenosis. Significant differences in baseline blood flow velocity were present between patients with impaired CFR and without impaired CFR after PTCA in both balloon-treated patient group and stent-treated patient group.

Differences Between Patients With Impaired CFR (≤2.5) and Without Impaired CFR (>2.5) After PTCA in the Balloon-Treated Patient Group Without Restenosis

In the stent-treated group, 8 of 19 patients demonstrated impaired CFR after balloon angioplasty. After stent implantation, impaired CFR and rCFR improved toward values within the range of the reference coronary artery (from 2.0±0.2 to 2.7±0.9 and from 0.68±0.19 to 0.89±0.21, respectively; both P=0.07). These alterations were related to a nonsignificant increase of the hyperemic blood flow velocity (45±14 to 54±23 cm/s; P=0.18), whereas the baseline blood flow velocity remained unchanged after stent implantation (23±7 to 23±14 cm/s).

Impaired CFR After Stent Implantation

Immediately after stent implantation, 11 patients demonstrated an impaired CFR (2.0±0.3; Table 4⇓, Figure 3A⇑). None of these patients developed restenosis at follow-up. Impaired CFR after stent implantation improved at follow-up toward values documented in patients without impaired CFR after stent implantation (Table 4⇓). Impaired CFR was related to a transient increase of the baseline APV after stent implantation compared with patients without impaired CFR (Figure 4⇑, Table 4⇓). In patients with impaired CFR after stent implantation, the angiographic variables and adenosine-induced hyperemic APV were similar to those values in patients without impaired CFR and remained similar at follow-up (Figure 4⇑, Table 4⇓).

Differences Between Patients With Impaired CFR (≤2.5) and Without Impaired CFR (>2.5) After Stent Implantation in Stent-Treated Patient Group

Impaired rCFR After PTCA

The rCFR cutoff value was determined to be 2.5/3.1=0.80 (Figure 1⇑). Patients with an impaired rCFR (≤0.80) after PTCA demonstrated results similar to those of patients with impaired CFR (≤2.5) after PTCA; ie, a transient increase of the baseline blood flow velocity compared with those patients without impaired rCFR (>0.80) in the balloon-treated patient group (26±20 cm/s, n=9, versus 14±4 cm/s, n=18; P<0.05) and in the stent-treated patient group (33±18 cm/s, n=10, versus 18±9 cm/s, n=9; P<0.05).

Discussion

This study demonstrates an overall immediate improvement of absolute and relative CFR toward normal values after balloon angioplasty. Despite the additional lumen enlargement as determined by angiographic variables, there was no further improvement of the absolute and relative CFR after stent implantation. Impaired CFR immediately after successful balloon angioplasty or stent implantation was related to an increase in baseline blood flow velocity. Individual values of distal CFR changed at follow-up in patients without restenosis; ie, at follow-up, initial high values decreased and low values increased toward values of the reference CFR. Normalization of impaired CFR at follow-up in patients without restenosis after balloon angioplasty or stenting was associated with a decline of the baseline blood flow velocity toward values seen in patients without impaired CFR, supporting the contention that this phenomenon is predominantly related to a slow recovery of autoregulation of the microvascular bed.

Immediate Effect on CFR After Balloon Angioplasty or Stent Implantation

In this study, the average CFR improved immediately after balloon angioplasty to a value that was within the range of the CFR of the normal reference coronary artery. This improvement after balloon angioplasty is in accordance with the findings of several other studies evaluating myocardial or coronary flow reserve using digital subtraction angiography,14 PET,15 or distal blood flow velocity measurements.36

Impaired CFR After PTCA

In the balloon-treated patients as well as in the stent-treated patient group, an impaired CFR was related to a higher baseline blood flow velocity, whereas the adenosine-induced hyperemic response was similar to that of patients without impaired CFR. These findings are in accordance with other studies that demonstrated an impaired coronary flow reserve immediately after balloon angioplasty, compared with normal values of the control group, due to an increased baseline coronary blood flow.1016 Several mechanisms have been postulated for the observed increase in baseline flow velocity after PTCA, such as (1) failure of the peripheral arterial vascular bed to vasoconstrict appropriately on the sudden increase in distal coronary pressure produced by coronary angioplasty, (2) epicardial vasoconstriction at the site of the Doppler guidewire tip mediated by a myogenic response and/or neural mechanisms,1718 or (3) the influence of drug therapy.1920 However, all patients were treated with nitroglycerin during the procedure, and there was no difference in drug therapy (nitrates, calcium antagonists, β-blockers, or ACE inhibitors) between patients with and without impaired CFR after PTCA. Finally, baseline blood flow velocity can still be elevated by the hyperemic response after balloon occlusion. The hyperemic effect of balloon occlusion should be minimal after the 10 minutes that we used as the time period between the balloon occlusion and the blood flow velocity measurements. Nevertheless, the precise mechanism responsible for the elevated baseline blood flow velocity immediately after PTCA remains unelucidated and requires further investigation.

A residual epicardial stenosis may be responsible for an impaired CFR after balloon angioplasty due to a reduction in adenosine-induced hyperemic blood flow velocity. This is illustrated in patients with impaired CFR after balloon angioplasty in the stent-treated patient group. High-pressure stent implantation resulted in augmentation of the angiographic lumen in conjunction with an immediate increase of the absolute and relative CFRs. This improvement in CFR was achieved by an increase of the adenosine-induced hyperemic response after stent implantation while the baseline flow velocity remained unchanged. This phenomenon was also reported by other studies, suggesting an important role of residual lumen obstruction for impaired CFR after balloon angioplasty.78 Nevertheless, the mean CFR for the whole patient group remained unchanged after stent implantation as a result of a variable response in CFR, ie, 9 of 19 patients showed an increase and 10 patients showed a decrease.

Long-Term Effect of Balloon Angioplasty and Stent Implantation

Several studies reported a delayed recovery of impaired coronary flow reserve at follow-up toward the higher reference values of control subjects.91122 Improvement of the impaired myocardial or coronary flow reserve was considered to be related to a temporarily increased baseline value or a temporarily impaired hyperemic blood flow immediately after angioplasty22 or potentially related to an improvement of the stenosis geometry at follow-up.9 Our results described a long-term response after balloon angioplasty similar to that found after stent implantation (Figure 3⇑). This indicates that the long-term adaptation of the CFR toward normal reference values is not due to epicardial remodeling at the site of the lesion. In this respect, our findings are not in agreement with the findings of Zijlstra et al,9 who reported that an increase of CFR was associated with an improvement in arterial luminal dimensions. Furthermore, patients with impaired CFR after PTCA demonstrated a decrease of the high baseline blood flow velocity at follow-up toward the baseline values of patients without impaired CFR (Figure 4⇑). These findings emphasize the important role of the slow recovery of autoregulation in explaining the transiently impaired CFR immediately after PTCA.

Relative CFR

The present study shows the long-term effect of PTCA on the distal CFR, revealing “normalization” toward values of the reference coronary artery in patients without restenosis. At present, the literature regarding the effect of PTCA on CFR is restricted to the analysis of the dilated coronary artery. Nevertheless, CFR measurements are subject to a high interpatient variability that is related to a variety of physiological2324 and pathophysiological conditions.252627 The absolute CFR ≤2.5 as a definition of impaired CFR after PTCA is based on data obtained in a selected patient population. A CFR >2.5 after successful PTCA is in accordance with a rCFR >0.80 (Figure 1⇑). This value is in agreement with a study by Kern et al28 yielding rCFR of >0.81 after stent implantation in all patients, including a subset with impaired CFR of the reference vessel. The use of rCFR may be important in those patients with an impaired CFR related to the aforementioned (patho-)physiological conditions.829 The present study suggests that a CFR of 2.0, used as a cutoff value for diagnostic purposes in several studies, is in accordance with an rCFR of 0.60 (Figure 1⇑). Nevertheless, the role of the rCFR for diagnostic and therapeutic purposes is at present the subject of study in multicenter trials.

Limitations of the Study

Intracoronary blood flow velocity assessment is a sensitive technique for the detection of alterations in coronary blood flow, but this method is also prone to technical failures, and accurate measurements depend on the time, skill, and experience of the cardiologist.

The site of the repeated blood flow velocity measurements was determined by angiography, although this method for making repeated measurements may have been a contributing factor in the variations noted. Moreover, these single-center results were obtained in a uniform selected group of patients, which limits extrapolation to other patient categories or other institutions.

The reference CFR was measured only immediately after PTCA and at late follow-up to calculate the relative CFR. The reference CFR was not measured before PTCA, although recent studies indicate that this limitation is not a major drawback of the present study.930

In the present study, the role of remodeling in the normalization process of the CFR was limited, on the basis of long-term normalization effects in patients treated with balloon angioplasty similar to those treated with stent implantation (Figure 4⇑). However, complete evaluation of remodeling cannot be judged without intravascular ultrasound, which was not performed in the present study.31

Furthermore, this study was not designed to evaluate the time period of improvement of the distal CFR after PTCA. Several studies implied a normalization of the average coronary vasodilatory reserve within 3 months.2232

Clinical Implications

Patients with impaired CFR after balloon angioplasty may benefit from additional stent implantation instead of omitting adjunct intervention; ie, better long-term angiographic and hemodynamic results and less restenosis at follow-up. For this reason, assessment of the CFR and/or CFR directly after angiographically satisfactory balloon angioplasty can be a cost-effective tool for decision making regarding adjunctive stenting. However, the limited number of patients studied precludes conclusions regarding the selection of patients with impaired CFR after balloon angioplasty who may benefit from additional stent implantation. This clinically relevant issue is currently being evaluated in multicenter studies involving larger cohorts of patients (DEBATE 2 and DESTINI study).

Acknowledgments

This study was supported by the Netherlands Heart Foundation, the Hague, Netherlands (grant 95.179). Dr Piek is a clinical investigator for the Netherlands Heart Foundation (grant D96.020). We gratefully acknowledge the technical and nursing staff of our Cardiac Catheterization Laboratory (chief: Peter J. Belgraver, RN) for skilled assistance. We thank Morton J. Kern, MD (J.G. Mudd Cardiac Catheterization Laboratory, St Louis University Hospital) for his helpful suggestions during the conduct of this study.

Zijlstra F, den Boer A, Reiber JHC, van Es GA, Lubsen J, Serruys PW. Assessment of immediate and long-term functional results of percutaneous transluminal coronary angioplasty. Circulation.1988;78:15–24.Patients with 1-vessel disease were studied to evaluate the immediate and long-term effects of balloon angioplasty (n=34) or stent implantation (n=20) on the coronary flow velocity reserve (CFR). In both patient groups, high CFR values after PTCA decreased and impaired CFR (≤2.5) values after PTCA increased at follow-up toward the values of the reference CFR in patients without restenosis. A transiently impaired CFR after PTCA was a frequent finding and was a result of a high baseline flow velocity after PTCA that normalized at follow-up, supporting the contention that this phenomenon relates to a slow recovery of the microvascular autoregulation.